LDL-Controlling Protein Exerts Effect Extracellularly

Findings appearing in the Journal of Biological Chemistry suggest that PCSK9 acts primarily as a secreted factor.!--h2>

A protein responsible for regulating LDL cholesterol in the blood works almost exclusively outside cells, according to researchers at the University of Texas (UT) Southwestern Medical Center.

It is well known that PCSK9, which is made and secreted in the liver, degrades low-density lipoprotein receptors (LDLRs) in the liver by binding to the epidermal growth factor-like repeat A (EGF-A) domain. This triggers a chain of biochemical reactions that leads to the destruction of the LDL receptor.

Previous studies by the UT Southwestern investigators showed that in mice lacking PCSK9, LDL cholesterol levels are less than half those of normal mice. Additionally, they’ve found that people with mutations in the PCSK9 gene that prevented them from making normal levels of the protein had LDL cholesterol levels 28% lower than individuals without the mutation and were protected from developing coronary heart disease.

The current research sought to understand whether PCSK9 causes degradation of LDLRs within the secretory pathway or following secretion and reuptake via endocytosis. Results are published in a paper called “Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells,” available in the Journal of Biological Chemistry.

The UT team showed that a mutation in the LDLR associated with hypercholesterolemia increases the sensitivity to exogenous PCSK9-mediated cellular degradation. Additionally, the researchers added LDLR subfragments to a medium of liver cells stably overexpressing wild-type PCSK9 or gain-of-function PCSK9 mutants associated with hypercholesterolemia. These subfragments blocked secreted PCSK9 binding to cell surface LDLRs and resulted in the recovery of LDLR levels to those of control cells.

Thus, the scientists concluded that PCSK9 acts primarily as a secreted factor, or externally, to cause LDLR degradation. They suggest that pharmacological inhibition of the PCSK9-LDLR interaction extracellularly will increase hepatic LDLR expression and lower plasma low density lipoprotein levels.